Proteases have crucial roles in homeostasis and disease; and protease inhibitors and recombinant proteases in enzyme replacement therapy have become key therapeutic applications of protease biology across several indications. This review briefly summarises therapeutic approaches based on protease activation and focuses on how recent insights into the spatial and temporal control of the proteolytic activation of growth factors and interleukins are leading to unique strategies for the discovery of new medicines. In particular, two emerging areas are covered the first is based on antibody therapies that target the process of proteolytic activation of the pro-form of proteins rather than their mature form; the second covers a potentially new class of biopharmaceuticals using engineered, proteolytically activable and initially inactive pro-forms of antibodies or effector proteins to increase specificity and improve the therapeutic window.

Aortic stenosis (AS) and acute coronary syndrome (ACS) share similar cardiovascular risk factors. The incidence of concomitant AS and ACS is increasing with aging population, yet studies investigating the prognosis of these patients remain scarce.

This retrospective single-centre cohort study examined consecutive patients who presented with ACS and AS from January 1, 2011, to March 31, 2021. The cohort was divided into mild, moderate, and severe AS based on the index echocardiogram. The primary outcome was all-cause mortality.

Of 563 patients, 264 (46.9%) had mild, 193 (34.3%) moderate, and 106 (18.8%) severe AS. The mean follow-up duration was 2.5 years. All-cause mortality was higher among patients with moderate and severe AS compared with mild AS within 30 days (17.0% vs 13.0% vs 6.4%, respectively; P= 0.005) and in the long term (49.7% vs 51.4% vs 35.6%; P= 0.002). Concomitant moderate (hazard ratio [HR] 1.453, 95% confidence interval [CI] 1.020-2.068; P= 0.038) or severe AS (HR 1.873, 95% CI 1.176-2.982; P= 0.008) was an independent predictor of all-cause mortality. Kaplan-Meier curves demonstrated higher mortality in patients with moderate and severe AS compared with mild AS (P < 0.001). Similar survival trends were observed regardless of ACS type and in those with preserved left ventricular ejection fraction. Patients with reduced left ventricular ejection fraction had poor prognosis regardless of AS severity.

ACS patients with concomitant moderate or severe AS have similar high long-term mortality, regardless of ACS type. The high early mortality in moderate and severe AS emphasises the imperative to attempt to mitigate this risk urgently.

ACS patients with concomitant moderate or severe AS have similar high long-term mortality, regardless of ACS type. The high early mortality in moderate and severe AS emphasises the imperative to attempt to mitigate this risk urgently.Ventricular assist devices (VADs) are being increasingly used to support patients with congenital heart disease and single-ventricle physiology. Because of their unique anatomy and physiology, special consideration must be used to provide effective mechanical circulatory support for each individual patient. This can include alternative cannulation techniques, strategies to balance cardiac output to the systemic and pulmonary circulations from a single ventricle, or the use of continuous vs pulsatile VADs for better ventricular offloading. In this article we review the etiology of single-ventricle failure, VAD options for support, cannulation strategies, post-VAD management considerations, and outcomes at each of the 3 stages of palliation.Plastic bronchitis (PB) and protein-losing enteropathy (PLE) are rare but potentially devastating complications of the Fontan circulation. PB occurs in ∼4% of Fontan patients, typically presents within 2 to 3 years of Fontan completion with chronic cough, wheezing, fever, or acute asphyxiation, and is characterised by proteinaceous airway casts that are expectorated or found on bronchoscopy. PLE develops in 4% to 13% of patients, usually within 5 to 10 years post Fontan, and manifests with edema, ascites, hypoalbuminemia, lymphopenia, hypogammaglobulinemia, and elevated fecal alpha-1 antitrypsin 1. These disorders have similar pathophysiology involving disruption of the lymphatic system resulting from elevated central venous pressure combined with elevated lymphatic production and inflammation, resulting in lymphatic drainage into low-pressure circuits such as the airways (PB) and duodenum (PLE). Our understanding of these disorders has greatly improved over the past decade as a result of advances in imaging of the lymphatic system through magnetic resonance lymphangiography and early success with lymphatic interventions including lymphatic embolisation, thoracic duct embolisation, and percutaneous thoracic duct decompression. Both PB and PLE require a multidisciplinary approach that addresses and optimises residual hemodynamic lesions through catheter-based intervention, lowers central venous pressure through medical therapy, minimises symptoms, and targets abnormal lymphatic perfusion when symptoms persist. This review summarises the pathophysiology of these disorders and the current evidence base regarding management, proposes treatment algorithms, and identifies future research opportunities. Key considerations regarding the development of a lymphatic intervention program are also highlighted.

Data are limited regarding differential and common effects of cardiovascular risk factors on subclinical changes in vascular structure and function. We aimed to examine the relationships of life-course cumulative burdens of cardiovascular risk factors with adult arterial pulse wave velocity (PWV) and carotid intima-media thickness (CIMT) in a longitudinal cohort of the Bogalusa Heart Study.

The cohort consisted of 900 subjects who had aortic-femoral PWV and CIMT measurements. These participants were examined 5-16 times for body mass index (BMI), blood pressure, atherogenic index of plasma (AIP), and low-density lipoprotein cholesterol (LDLC) from childhood to adulthood. The area under the curve (AUC) was calculated as a measure of long-term burden of the risk factors.

Adjusting for covariates, adult PWV was associated with AUCs of BMI, systolic blood pressure (SBP) and AIP (standardized regression coefficient [β]= 0.191, 0.321, 0.153, respectively; P < 0.001 for all). Adult CIMT was associated with AUCs of BMI, SBP, AIP and LDLC (β= 0.115, 0.202, 0.141, 0.152, respectively; P < 0.001 for all). Moreover, childhood BMI was associated with adult PWV and CIMT (β= 0.088 and 0.075, respectively; false discovery rate q values < 0.05 for both), and childhood LDLC with adult CIMT (β= 0.079; false discovery rate q value < 0.05). These associations did not differ significantly among race and sex groups.

The life-course cumulative burden of BMI, SBP, and AIP has common effects on arterial wall stiffening and thickening, whereas LDLC is specifically associated with arterial wall thickness, and this effect starts in early life.

The life-course cumulative burden of BMI, SBP, and AIP has common effects on arterial wall stiffening and thickening, whereas LDLC is specifically associated with arterial wall thickness, and this effect starts in early life.Paeonol, a naturally occurring polyphenol isolated from medical plant, has been known to exhibit anti-oxidative and anti-inflammatory effects. In order to evaluate the effect of paeonol on Carassius auratus gibelio infected by pathogenic bacteria Aeromonas hydriphila. 750 fish were randomly divided into 5 groups, which separately treated with 0.85% sterile saline (blank), A. hydriphila (negative control), A. hydriphila with paeonol (4 mg/kg, 64 mg/kg), and A. hydriphila with enrofloxacin (12 mg/kg, positive control). Fish were anaesthetized with MS-222 (100 mg/L), and samples were collected at 6 and 72 h after A. hydriphila challenge. The results showed that compared with the negative group, the survival in paeonol groups marked increased by 14.75% and 18.94%. The plasma immunoglobulin M (IgM) was notably increased, and low density lipoprotein (LDL) was significantly decreased in paeonol groups at 6 h (P less then 0.05). The antioxidative enzymes catalase (CAT), total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) were significantly increased in paeonol groups at 6 h, while malondialdehyde (MDA) and myeloperoxidase (MPO) contents were lower (P less then 0.05). The inflammatory related genes MyD88 and TLR-5 were significantly downregulated, and the TLR-3 was significantly increased in paeonol groups at 72 h (P less then 0.05). In addition, histopathological analyses showed that the lesion in liver, spleen and caudal kidney were considerably attenuated in paeonol groups. In conclusion, paeonol could increase the survival rate, mitigate oxidative damage, inflammation, tissue lesions, and improve the immunity of gibel carp challenged with A. hydrophila.The phagocytic actives of B cells in fish have been proven in recent years. In this study, five positive hybridomas secreting monoclonal antibodies (MAbs) against largemouth bass IgM were produced. Indirect immunofluorescence assay (IFA) demonstrated that five MAbs could specifically recognize membrane-bound IgM (mIgM) molecule of largemouth bass. Indirect ELISA and Western blotting analysis showed that all the five MAbs had no cross-reactions with the other two teleost IgMs. Flow cytometry analysis (FCM) revealed that the percentages of largemouth bass mIgM+ lymphocytes in head kidney, peripheral blood and spleen were 51.66 ± 0.608%, 16.5 ± 1.235% and 42.92 ± 1.091%, respectively. In addition, the phagocytosis rates of mIgM + lymphocytes ingesting Nocardia seriolae from head kidney, peripheral blood and spleen were calculated to be 5.413 ± 0.274%, 16.6 ± 0.289% and 26.3 ± 0.296%, respectively. The qPCR results of sorted cells indicated that most inflammatory cytokines (IFNγ, IL-1β, IL-2, IL-12β, IL-34, IL-10), chemokine (CXCL12), chemokines receptors (CXCR2, CXCR4) and genes (FcγRⅠa, NCF1, CFL, ARP2/3, CD45, Syk, MARCKS) related to FcγR-mediated phagocytic signaling pathway in phagocytic mIgM+ lymphocytes were up-regulated significantly (P less then 0.05). Taken together, the results suggested that the MAb (MM06H) produced in this paper could be used as a tool to study mIgM+ lymphocytes of largemouth bass, and FcγR may participate in the phagocytosis of mIgM+ lymphocytes, which is helpful to further study the role of mIgM+ lymphocytes in innate immunity.Propolis is non-hazardous resinous substance mixture containing bioactive ingredients such as polyphenols, flavonoids and organic acid. It has been widely used as food supplement and immune adjuvant due to its benefits in anti-microbial and immunomodulation. Edwardsiella piscicida is a kind of threatening pathogen which could cause high mortality in turbot. However, whether propolis could enhance the innate immune response against E. piscicida infection in turbot remains unknown. In this study, we found dietary propolis addition could improve the expression of anti-oxidative stress related enzymes, e.g., SOD, CAT and GPT, and relieved the histopathological changes of juvenile turbot after E. piscicida infection. Moreover, propolis addition increased the expression of cytokines such as il-1β, il-6 and tnf-α in different organs of juvenile turbot. Importantly, rescued survival and decreased bacterial loads were observed in propolis feeding group. Taken together, these findings suggest that the important roles of propolis in protecting juvenile turbot from E.